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J. Biol. Chem., Vol. 277, Issue 42, 39703-39712, October 18, 2002
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From the Department of Medicine, University of California, San
Francisco, and the Endocrine Unit, Veterans Affairs Medical Center,
San Francisco, California 94121
In this study we have examined the
interaction between CD44 (a hyaluronan (HA) receptor) and the
transforming growth factor
Hyaluronan Promotes Signaling Interaction between CD44 and the
Transforming Growth Factor
Receptor I in Metastatic Breast
Tumor Cells*
,
(TGF-) receptors (a family of
serine/threonine kinase membrane receptors) in human metastatic breast
tumor cells (MDA-MB-231 cell line). Immunological data indicate that
both CD44 and TGF- receptors are expressed in MDA-MB-231 cells and
that CD44 is physically linked to the TGF- receptor I (TGF-RI)
(and to a lesser extent to the TGF- receptor II (TGF-RII)) as a
complex in vivo. Scatchard plot analyses and in
vitro binding experiments show that the cytoplasmic domain of
CD44 binds to TGF-RI at a single site with high affinity (an
apparent dissociation constant (Kd) of ~1.78
nM). These findings indicate that TGF-RI contains a
CD44-binding site. Furthermore, we have found that the binding
of HA to CD44 in MDA-MB-231 cells stimulates TGF-RI serine/threonine
kinase activity which, in turn, increases Smad2/Smad3 phosphorylation
and parathyroid hormone-related protein (PTH-rP) production (well known
downstream effector functions of TGF- signaling). Most importantly,
TGF-RI kinase activated by HA phosphorylates CD44, which enhances
its binding interaction with the cytoskeletal protein, ankyrin, leading to HA-mediated breast tumor cell migration. Overexpression of TGF-RI
by transfection of MDA-MB-231 cells with TGF-RIcDNA stimulates formation of the CD44·TGF-RI complex, the association of
ankyrin with membranes, and HA-dependent/CD44-specific
breast tumor migration. Taken together, these findings strongly suggest
that CD44 interaction with the TGF-RI kinase promotes activation of
multiple signaling pathways required for ankyrin-membrane interaction,
tumor cell migration, and important oncogenic events (e.g.
Smad2/Smad3 phosphorylation and PTH-rP production) during HA and
TGF--mediated metastatic breast tumor progression.
*
This work was supported in part by United States Public
Health Service Grants CA66163 and CA78633 and Department of Defense Grant DAMD 17-99-1-9291.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence and reprint requests should be addressed:
Endocrine Unit (111N), Dept. of Medicine, University of California, San
Francisco, and Veterans Affairs Medical Center, 4150 Clement St., San
Francisco, CA 94121. Tel.: 415-221-4810 (Ext. 3321); Fax: 415-383-1638;
E-mail:lillyb@itsa.ucsf.edu.
§
Supported by an American Heart Association predoctoral fellowship.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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